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PubMed1986

C5a fragment of bovine complement. Purification, bioassays, amino-acid sequence and other structural studies.

C5a and des-Arg-C5a have been purified from bovine serum in milligram amounts. The progress of the purification was followed by measuring the chemotactic activity of the complement fragments. The two polypeptides induce activation of neutrophil-oriented locomotion and secretion with very similar dose/response effects. After preparing a rabbit antiserum to bovine C5a/des-Arg-C5a, a competitive enzyme-linked immunosorbent assay (ELISA) was set up for the detection of C5a from 5 ng/mol to 1 microgram/ml. The complete primary structure of bovine C5a, which consists of 74 amino acids, has been determined by sequence analysis of the tryptic peptides, aligned by peptides derived from a chymotryptic digest, and by partially sequencing the intact molecule. Bovine C5a has a sequence homology of 78% and 70% with porcine and human C5a, respectively, reacts with an antiserum to porcine C5a and is recognized by cell surface receptors on human neutrophils. Finally, the secondary structure of bovine C5a was investigated by circular dicroic spectroscopy and predicted from the amino acid sequence. A comparison of the content and distribution of alpha-helical and/or hydropathic regions, suggests that the three-dimensional structure of C5a might be modeled from the known crystal structure of the homologous C3a molecule.

Amino Acid Sequence↗
PubMed1987

Airway responses in vitro following C5a des Arg-induced hyper-responsiveness in vivo in rabbits.

The mechanism of C5a des Arg-induced airway hyper-responsiveness in rabbits was investigated. Airway smooth muscle from rabbits which had been pretreated in vivo, was studied in vitro. Tracheal rings, segmental bronchial rings, subsegmental bronchial spirals and lung parenchymal strips were all prepared from each rabbit lung. Although C5a des Arg produces hyper-responsiveness to histamine in vivo, which is inhibited by indomethacin, the airway smooth muscle responses in vitro from control, C5a des Arg and C5a des Arg plus indomethacin pretreated rabbits did not differ. The neutrophil counts in the tracheal and subsegmental bronchial specimens were increased in the C5a des Arg-treated group. Indomethacin significantly (P less than 0.05) inhibited the neutrophil influx in the subsegmental bronchi. It is concluded that intrinsic smooth muscle function is unaltered following C5a des Arg-induced hyper-responsiveness in vivo.

Airway Resistance↗
PubMed1986

Chemotactic activity for polymorphonuclear and mononuclear leukocytes in rheumatoid synovial fluids.

In order to why polymorphonuclear leukocytes (PMNs) are predominant and mononuclear leukocytes (MNLs) are few in rheumatoid synovial fluids, chemotactic factor(s) for PMNs and MNLs were studied in the synovial fluids of rheumatoid arthritis (RA-SF) and osteoarthritis (OA-SF) using both Boyden's and agarose methods. The RA-SF showed strong chemotactic activity for human peripheral blood PMNs compared with non-rheumatoid OA-SF. The chemotactic activity for PMNs was well correlated with the number of PMNs in RA-SF, suggesting that it was a natural mediator for PMN emigration into rheumatoid joint cavity. The major chemotactic factor for PMN in RA-SF was of apparent molecular weight of 14,000 and its activity was suppressed to less than 10 percent by anti-C5a antibody, but it failed to show any anaphylatoxin activity which was an attribute of C5a. It was, therefore, suggested to be C5a-like molecule but not C5a itself. The possibility that the factor may be a C5a des-Arg was discussed. On the contrary, the chemotactic activity for MNLs was not found neither in RA-SF nor OA-SF. These findings may explain the fact that PMNs are predominant in rheumatoid synovial fluids.

Arthritis, Rheumatoid↗
PubMed1977

The complement system in infectious mononucleosis.

The complement system was investigated in 34 patients with infectious mononucleosis. Three had specific complications: one haemolytic anaemia, one severe arthralgia/myalgia and one proliferative glomerulonephritis. Complement changes consistent with classical pathway consumption were seen in ten of the uncomplicated group and the patients with haemolytic anaemia and arthralgia/myalgia. The patient with glomerulonephritis showed evidence of alternative pathway utilisation including C3 splitting activity and the deposition of properdin on renal biopsy. The complement findings suggest that circulating immune complexes are common in such patients and are likely to play a role in the pathogenesis of the complications. It is proposed that both complement pathways may be required for the effective clearance of viral material from the circulation.

Complement C1 Inactivator Proteins↗
PubMed1978

Alternative pathway of complement activation by Candida albicans.

Activation of the alternative pathway of complement by Candida albicans was examined using a chemotactic assay. Two serologically defined strains and eight clinical isolates of Candida albicans were used in these experiments. The results showed that all ten strains of Candida albicans were capable of alternative complement pathway activation. These findings may provide an insight into host resistance to this infection.

Candida albicans↗
PubMed1987

Release of leukotriene B4 from sublethally injured oligodendrocytes by terminal complement complexes.

In the present study, the interaction of the terminal complement complexes with oligodendrocytes was investigated for observation of its effect on membrane lipid hydrolysis. [14C]Arachidonic acid was incorporated into the membrane lipids of cultured oligodendrocytes before sensitization with anti-galactocerebroside antiserum. Cells were then exposed to excess C6-deficient rabbit serum reconstituted with limiting doses of C6 to form various numbers of C5b-9 complexes. Qualitative analysis of the supernatants by HPLC revealed the presence of compounds that coeluted with arachidonic acid and its oxygenated derivatives, prostaglandin E2, leukotrienes E4 and B4, and 15-hydroxyeicosatetraenoic acid. The kinetics of leukotriene B4 release by excess C5b-8 was quantitated by radioimmunoassay. Leukotriene B4 release approached a maximum around 30 min, and C6 dose-response studies performed at 1 h showed that maximal levels of leukotriene B4 were detected over a range of sublytic C5b-9 attack. Maximal release of leukotriene B4 was also achieved by C5b-8 without further enhancement by addition of lytic doses of C9. Results indicate that sublytic attack of oligodendrocytes by complement induces release of lipid-derived inflammatory mediators.

Animals↗
PubMed1985

Inflammatory oedema induced by synergism between calcitonin gene-related peptide (CGRP) and mediators of increased vascular permeability.

The potent vasodilator calcitonin gene-related peptide (CGRP, human synthetic), when mixed with histamine and injected intradermally in the rabbit, induced a marked potentiation of local oedema. CGRP also potentiated oedema induced by other mediators of increased microvascular permeability in the rabbit; bradykinin, platelet-activating factor (Paf), C5a des Arg, N-formylmethionyl-leucyl-phenylalanine (FMLP) and leukotriene B4 (LTB4). Substance P alone, or mixtures of substance P and CGRP, failed to induce oedema in rabbit skin. In rat skin, however, substance P induced oedema and this was potentiated by CGRP. CGRP had a protracted potentiating action following intradermal injection in the rabbit. The time for half loss of activity for CGRP was 40.1 +/- 7.5 min compared to 18 +/- 1 min for prostaglandin E2 (PGE2). No loss of potentiating activity was detected after incubation of CGRP in rabbit plasma or blood for 60 min. We postulate that endogenous CGRP, if released locally from nerve endings, could have a marked enhancing effect on oedema induced by other mediators in an inflammatory reaction.

Animals↗
PubMed1985

Effects of the C5a anaphylatoxin and its relationship to cyclo-oxygenase metabolites in rabbit vascular strips.

Strips of rabbit blood vessels were suspended in vitro and responses to complement peptides C3a and C5a were recorded isotonically. Human C3a (up to 1.5 microM) was inactive on rabbit vascular strips. Human C5a (2.9-59 nM) decreased spontaneous activity of the rabbit portal vein under resting baseline tension. The C5a relaxed strips of portal vein and pulmonary artery that were precontracted with noradrenaline (NA, 200 nM). On the portal vein, C5a-induced relaxation was preceded by a transient contractile phase which decreased with repeated applications of C5a. The magnitude of C5a-induced relaxation of both vessels increased with repeated stimulation by C5a. Maximal levels of relaxation for the third application of C5a at 59 nM averaged 44% and 17% of the NA-induced contraction plateau in portal vein and pulmonary artery, respectively. Strips of rabbit aorta responded minimally to C5a. Indomethacin (5.6 microM) significantly inhibited C5a-induced relaxation of the portal vein and pulmonary artery but had no effect on the early contractile response of the portal vein. Mepyramine (10 microM) failed to modify the C5a response from either vessel, but it reduced the contractile phase of the C5a response on the portal vein when applied in conjunction with indomethacin. The drug SKF 88046, an end organ antagonist of thromboxane (TX) A2 and some contractile prostaglandins, reduced the contractile phase and increased relaxation of the portal vein to C5a but did not modify the response of the pulmonary artery. Radioimmunoassays for 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and TXB2 were performed on the fluid bathing rabbit isolated blood vessels. C5a promoted release of 6-keto-PGF1, over the basal release rate in rabbit tissues. Only trace quantities of TXB2 were produced by rabbit vessels exposed to C5a. 7 It is concluded that the mechanical response of blood vessels to C5a is mainly determined by the type of cyclo-oxygenase products released and by the sensitivity of each blood vessel to these active lipids. Tissue histamine release is also responsible for a component of the response of rabbit portal vein to C5a. The relaxant effect of C5a on rabbit blood vessels may be a phenomenon related to the previously reported hypotensive action of classical anaphylatoxins in vivo.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Kinetics of the generation and action of chemical mediators in zymosan-induced inflammation of the rabbit peritoneal cavity.

Acute inflammation was induced by intraperitoneal injection of zymosan (yeast cell walls) in the rabbit. Peritoneal inflammation was monitored by the local accumulation of intravenously-injected Evans blue dye (which binds to plasma albumin) and of polymorphonuclear leukocytes (PMNLs). The zymosan-induced exudate fluid contained a microvascular permeability-increasing factor or factors which, unlike histamine and bradykinin, had a long duration of action when tested in rabbit skin and was dependent on circulating PMNLs. Using radioimmunoassay, high levels of rabbit C5a, or C5a des Arg, were detected in the exudate fluid and accounted for much of the permeability-increasing activity, as judged by skin bioassay after separation on Sephadex G-100. The vasodilator prostaglandin, prostaglandin I2 (PGI2), was generated in the inflammatory reaction, as judged by the presence of high levels of 6-oxo-PGF1 alpha detected in the exudate by radioimmunoassay. However, in contrast to observations in rabbit skin, inhibition of prostaglandin generation had a relatively small effect on peritoneal oedema formation. C5a and C5a des Arg increase microvascular permeability by a PMNL-dependent mechanism in the rabbit. However, in response to zymosan, protein leakage was detected considerably earlier than PMNL accumulation. A hypothesis to account for this difference is proposed.

Animals↗
PubMed1988

Prostacyclin biosynthesis and reduced 5-HT uptake after complement-induced endothelial injury in the dog isolated lung.

1. Pulmonary prostacyclin (PGI2) biosynthesis was evaluated in relation to endothelial integrity before and after complement activation in isolated plasma-perfused lung lobes of the dog. 2. The plasma was activated with zymosan (ZAP, n = 4), yeast cells (YAP, n = 4) or yeast with 3 microM indomethacin (Indo + YAP, n = 3). Immunoreactive 6-oxo-prostaglandin F1 alpha (i-6-oxo-PGF1 alpha) and thromboxane B2 (iTXB2) were measured to monitor PGI2 and TXA2 biosynthesis. 3. The kinetic parameters Km and Vmax of 5-hydroxytryptamine (5-HT) uptake were calculated on the basis of multiple indicator diffusion data to evaluate endothelial integrity. 4. YAP and ZAP induced a biphasic increase of the arterial perfusion pressure. The immediate pressure peak was partly mediated by TXA2 and the TXB2 was subsequently cleared by the lung. 5. The apparent Vmax of 5-HT uptake remained constant throughout the experiment. Thus, complement activation did not affect the number of endothelial 5-HT carrier sites available to the perfusate. 6. The apparent Km of 5-HT uptake was enhanced in 9 lungs exposed to activated plasma complement for 20 min. This decreased affinity for 5-HT probably reflects endothelial injury. It was transient as the apparent Km had returned to the baseline value after 60 min. 7. PGI2 clearance and biosynthesis were virtually absent in the control period. PGI2 formation increased drastically after infusion of ZAP or YAP and was proportional to the endothelial injury expressed as elevated Km or pulmonary oedema. Thus, PGI2 biosynthesis might be a marker of severe endothelial distress.

Animals↗
PubMed1987

Complement activation during hemodialysis: laboratory evaluation of hemodialyzers.

A laboratory method that facilitates delineation of the complement-activating characteristics of various dialyzers under defined conditions has been developed. Results obtained by circulating reconstituted human serum through these devices and measuring time-dependent production of both C3a and C5a antigens are entirely consistent with previous clinical observations. For example, the complement-activating potential of dialyzer membranes could be described as high (cuprammonium cellulose), moderate (cellulose acetate), or low (polycarbonate or polyacrylonitrile). Furthermore, these techniques provided the opportunity to identify membrane characteristics that are not readily defined by clinical studies alone. Specifically, membranes that transported and absorbed C5a antigen were readily identified by these methods. Additionally, laboratory evaluation provided the unique ability to define the efficiency of complement activation taking place on the membrane surface. Results of these investigations are compatible with a hypothetical model that not only describes the properties of a typical dialyzer membrane but may be generally applicable to other biomaterials as well.

Acrylic Resins↗
PubMed1987

Is contact activation of the coagulation system involved in the genesis of the first-use syndrome?

A number of mechanisms have been thought to be involved in the pathogenesis of the first-use syndrome. These include IgE antibody-mediated response to ethylene oxide-related antigens, membrane activation of the alternative complement pathway, activation of tissue mast cells and basophils by materials released from the dialyzer into the circulation, and transfer of bacterial products through high flux dialyzer. However, the possible role of the activation of blood coagulation system and platelets during dialysis has not been considered. The present communication reviews the theoretical basis for a possible connection between dialysis-induced activation of platelets and coagulation system with the first-use syndrome. Although the available data concerning the activation of intrinsic coagulation pathway during dialysis are conflicting, there is no controversy as to the occurrence of platelet activation. It is suggested that biochemical events triggered by activation of these systems may in part contribute to the genesis of first-use syndrome.

Anaphylaxis↗
PubMed1988

Complement activation produced by biomaterials.

The complement-activating potential of biomaterials may be defined by appropriate application of C3a and C5a anaphylatoxin radioimmunoassays. Studies performed with hemodialysis membranes demonstrate that blood contact with these model biomaterials results in complement activation that may be ascribed to specific properties of the material surface. Further delineation of these chemical and physical properties may permit design of biocompatible materials.

Anaphylatoxins↗
PubMed1983

Leishmania: chemotaxic responses of promastigotes and macrophages in vitro.

Promastigotes of Leishmania move progressively up a concentration gradient of: various sugars, specific sugars attracting individual species of Leishmania; serum albumin and another unidentified constituent of serum; hemoglobin; and a factor generated by promastigotes in NNN medium. The movement of promastigotes up a concentration gradient of serum is optimal at a pH of 6.4 to 6.8 and a temperature of 28 degrees C and above. Cholinergic and adrenergic agents did not affect the attraction of serum for promastigotes, and cyclic nucleotides, inflammatory mediators, and macrophage products were not chemotaxic. It is postulated that the sugar chemotaxins influence the movement of promastigotes from the sand fly midgut to the esophagus, and serum chemotaxins may play a part in the entry of promastigotes into the skin of a mammal from the proboscis. Macrophages, the host cell of the obligate intracellular Leishmania species, were not attracted to any product of promastigotes. When, however, promastigotes interact with serum, complement is activated to form C5a which is chemotaxic for macrophages. Activation of complement by promastigotes is, at least partially, by the alternate pathway. Other chemotaxins resulting from promastigote interaction with serum may also be present. Promastigotes may also produce inhibitors of C5a activity.

Amino Acids↗
PubMed1988

The role of black-pigmented Bacteroides in human oral infections.

Today, 10 black-pigmented Bacteroides (BPB) species are recognized. The majority of these species can be isolated from the oral cavity. BPB species are involved in anaerobic infections of oral and non-oral sites. In the oral cavity, BPB species are associated with gingivitis, periodontitis, endodontal infections and odontogenic abscesses. Cultural studies suggest a specific role of the various BPB species in the different types of infection. Bacteroides gingivalis is closely correlated with destructive periodontitis in adults as well as in juveniles. Bacteroides intermedius seems to be less specific since it is found in gingivitis, periodontitis, endodontal infections and odontogenic abscesses. The recently described Bacteroides endodontalis is closely associated with endodontal infections and odontogenic abscesses of endodontal origin. There are indications that these periodontopathic BPB species are only present in the oral cavity of subjects suffering from periodontal breakdown, being absent on the mucosal surfaces of subjects without periodontal breakdown. BPB species associated with healthy oral conditions are Bacteroides melaninogenicus, Bacteroides denticola and Bacteroides loescheii. There are indications that these BPB species are part of the normal indigenous oral microflora. Many studies in the past have documented the pathogenic potential and virulence of BPB species. This virulence can be explained by the large numbers of virulence factors demonstrated in this group of micro-organisms. Among others, the proteolytic activity seems to be one of the most important features. Several artificial substrates as well as numerous biological proteins are degraded. These include anti-inflammatory proteins such as alpha-2-macroglobulin, alpha-1-antitrypsin, C3 and C5 complement factors and immunoglobulins. B. gingivalis is by far the most proteolytic species, followed by B. endodontalis. Like other bacteria, the lipopolysaccharide of B. gingivalis has shown to be active in bone resorption in vitro and is capable in stimulating interleukin-1 production in human peripheral monocytes. Based on the well documented association with periodontal disease and the possession of relevant virulence factors, BPB species must be considered as important micro-organisms in the etiology of oral infections. B. gingivalis seems to be the most pathogenic and virulent species.

Bacteroides↗
PubMed1976

The natural modulation of the amplification phase of complement activation.

As C3 cleavage represents the most critical step in the elaboration of the biologic effects of the complement system, the modulation of this reaction by formation and function of the C3b-dependent C3 convertase may well determine whether the initial activation of the complement sequence eventuates in beneficial or detrimental effects to the host. Stabilization of the amplification C3b-dependent convertase, C3bBb, is achieved with P and C3NeF, respectively, after their binding which exhibits different molecular and temperature requirements. Control of this amplifying step occurs at three levels: intrinsic decay of the inherently labile C3bBb convertase; extrinsic decay by displacement of Bb from the convertase with beta1H; and inactivation by C3bINA of C3b after its generation from native C3 or removal of protective Bb by intrinsic or extrinsic decay. In the presence of the stabilizing factors the control proteins must function in sequence with beta1H-mediated decay preceding C3b inactivation.

Complement C3↗